Amlodipine 1a, and its salts are long-acting calcium channel blockers, and are thus useful for the treatment of cardiovascular disorders, such as angina, hypertension and congestive heart failure. The two enantiomers of amlodipine, and their salts, have different pharmacological profiles. The S-(-)-isomer is the more potent calcium channel blocker, and the R-(+)-isomer also exhibits activity in the treatment or prevention of atherosclerosis.
J. E. Arrowsmith et al in J.Med.Chem (1986) 29 1696, described the preparation of the two enantiomers of amlodipine via separation of the diastereotopic azide esters 1b, and J. E. Arrowsmith, in EPA 331315, disclosed the use of cinchonidine salts of acid 1c for the resolution of intermediates to eventually give enantiomerically pure amlodipine isomers. S. Goldman et al, in J.Med.Chem. (1992) 35 3341, described the chromatographic separation of diastereomeric amide isomers 1d. ##STR1##
None of the disclosed methods for resolution of amlodipine intermediates or derivatives offer an efficient and economic method susceptible of industrial application. Other methods of providing enantiomerically enriched amlodipine isomers are thus needed.
A recent review by S. Goldman et al, in Angew.Chem.Int.Edn.(Engl.) (1991) 30 1559, describes various methods of providing chiral 1,4-dihydropyridines in high enantiomeric excess (e.e.). This review paper, in section 2.2 (Resolution of Racemic Mixtures of Basic Dihydropyridine Derivatives), states that "Chiral acids such as camphorsulphonic acid and substituted tartaric acids have been used to separate the enantiomers of basic dihydropyridine derivatives in yields of up to 30%" (emphasis added). The use of these methods for the resolution of amlodipine into its enantiomers gave unsatisfactory results, in terms of both yield and enantiomeric purity. The "substituted tartaric acid" used most commonly in the reported methods was O,O'-dibenzoyltartaric acid, and various solvents, most commonly alcohols, were used with this reagent.